As global life expectancy and the prevalence of chronic diseases have increased, scientific research has delivered an expanding repertoire of treatments. An emerging challenge is ensuring the most effective, appropriate drug is selected early in each patient's journey. Aim: This study will determine whether a model that predicts response to treatments for psoriasis improves patient outcomes. Background: Psoriasis is a common, debilitating skin disease that affects between 2 and 4 in every 100 people worldwide. Patients develop red, scaly patches of skin that are itchy and painful. It is associated with heart and joint disease, can affect an individual's ability to work, and impacts on quality of life are comparable to heart disease or cancer. A third of patients report clinically significant anxiety and depression, and 1 in 10 have contemplated suicide. Recent research has led to several 'biologic' treatments for psoriasis, however almost one third of patients fail to respond. Biologics are prescribed in a 'trial and error' manner until disease control is achieved. This process is expensive, since biologics cost ~£10,000/year/patient. Current practice also places patients at risk of long periods with poorly controlled disease and exposure to drug side effects. It is therefore vital to understand which patients will benefit from a particular biologic. Since we now recognise that each patient has multiple unique characteristics (e.g. changes in their genetic code) that contribute to their psoriasis, there is an urgent need to use medications intelligently. The MRC-funded Psoriasis Stratification to Optimise Relevant Therapy (PSORT) study has uncovered markers of treatment response in psoriasis, however it is not known whether this knowledge will translate into better patient outcomes. Methods: Based on PSORT's findings, I will develop a model that predicts which biologic will be the most effective for a particular patient. The model will use information that is unique to the patient, including their genetic code ('DNA'; measured from a blood sample) and presence of arthritis. The model will then use blood tests (measuring drug levels) to guide dose adjustment during treatment. I will evaluate the model's accuracy by analysing an independent, multicentre psoriasis database called BADBIR, which has periodically followed up patients receiving biologics, and recorded detailed genetic and clinical information. I will next design an innovative clinical trial to determine whether the model will lead to better outcomes for patients, including clearance of psoriasis and improved quality of life. Patient and public involvement: I sought patient and public involvement (PPI) in the development of this study through focus groups and surveys supported by my collaborators the Psoriasis Association (the UK's leading national charity and membership organisation for individuals affected by psoriasis). I will set up a patient and public advisory panel and meet with PPI focus groups six-monthly to provide progress updates and ascertain feedback. Dissemination: The results will potentially significantly impact on patients and national clinical-care pathways, so all relevant stakeholders will be updated with key findings. I will disseminate results at national and international conferences and through high-impact peer-reviewed papers. Results will be broadcast via university press offices and the information channels of the Psoriasis Association (website, social-media, magazine). I will also highlight the importance of this research to other medical specialties prescribing biologics such as rheumatology and gastroenterology. It will thus help a wide range of patients with chronic immune-mediated diseases maintain better control of their health, and save money for the NHS.

Psoriasis is a common, chronic, potentially disfiguring disease that affects more than 1 million people in the UK. It can cause considerable psychological and social disability. In the past 10 years there has been a dramatic improvement in clinical outcomes for patients with severe psoriasis due to the introduction of a new class of injectable drugs called biologics. These work by targeting specific parts of the immune system which are important in causing psoriasis. However, these drugs are very expensive (estimated annual cost is £10,000) and it remains the case that a significant number of patients fail to respond adequately. If we could predict which patients will do well with a particular biologic drug then we could devise new treatment plans that would be personalised for each patient rather than the current system of "trial and error" prescribing. This would be of added benefit to society as a whole since it could result in significant cost savings to the NHS and aid the pharmaceutical industry in development of new drugs. The programme of research in the Psoriasis Stratification to Optimise Relevant Therapy (PSORT) consortium aims to use existing knowledge about psoriasis, both clinical and scientific, our unparalleled patient base coupled to involvement of patient organisations and state-of -the-art investigative tools to develop tests that we can use in the clinic to help direct personalised treatments. Specific questions we will ask are: i) do levels of a drug in the blood and a patient's immune response to that drug effect outcome; ii) are there specific changes in the skin and blood that predict which drug is likely to be more useful in a particular patient; iii) is there variation in a patient's genetic make-up, linked to psoriasis and how drugs work, that may predict response to treatment; and iv) does bringing all the information collected in i-iii above, though computer based data analysis, have more power to predict response to treatment? Successfully achieving such a goal requires a number of important criteria to be met. Perhaps most importantly we need consent from large numbers of patients to enter studies and provide samples of blood and skin. From the start of the study, we have engaged with the Psoriasis Association (patient organisation) to ensure the study met with their approval. As a consequence of patient engagement, in the UK we have arguably the world's leading safety registry for patients receiving biologic drugs for psoriasis. During the lifetime of our proposal, it will have accumulated comprehensive information on 7,000 patients including responses (good and bad) to biologics. The PSORT consortium includes representatives from 4 of the largest psoriasis clinics in the UK. These will provide the source for patient recruitment. The experiments will take advantage of several factors. First, in contrast to many other chronic diseases, change in psoriasis severity is simple and accurate to determine after starting therapy. Second, target organ tissue (i.e. skin) can be sampled in a minimally invasive way by skin biopsy (patient feedback tells us that this is acceptable to them). Third, internationally competitive expertise exists across the consortium between investigators and collaborators in all of the scientific disciplines required to successfully deliver the programme. Fourth, appropriate research infrastructure exist at each of the three main centres namely Manchester, Newcastle and London. This includes the registry itself (Manchester) and NHS funded facilities (Newcastle and London). Finally, we have developed an extensive network of pharmaceutical company partners who bring specific expertise and resources to the programme. Not only will this help in achieving the short term goals but it will also provide the necessary platform for translating the outcomes into clinically useful tests.